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Original Investigation
June 1, 2021

Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Allergy and Clinical Immunology, Chiba University Hospital, Chiba, Japan
  • 2Third Department of Internal Medicine, University of Yamanashi, Chuo, Japan
  • 3Department of Internal Medicine, Chiba Aoba Municipal Hospital, Chiba, Japan
  • 4Allergy and Clinical Immunology Center, Japanese Red Cross Narita Hospital, Narita, Japan
  • 5Department of Rheumatology, Shimoshizu Hospital, National Hospital Organization, Yotsukaido, Japan
  • 6Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
  • 7Department of Internal Medicine, Matsudo City Hospital, Matsudo, Japan
  • 8Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
  • 9Department of Rheumatology, Dokkyo Medical University, Tochigi, Japan
  • 10Department of Rheumatology, Yokohama Rosai Hospital, Yokohama, Japan
  • 11Department of Rheumatology, National Hospital Organization Chiba-East Hospital, Chiba, Japan
  • 12Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  • 13Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
  • 14Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Japan
  • 15Research Center for Allergy and Clinical Immunology, Asahi General Hospital, Chiba, Japan
  • 16Clinical Research Center, Chiba University Hospital, Chiba, Japan
JAMA. 2021;325(21):2178-2187. doi:10.1001/jama.2021.6615
Key Points

Question  Is a reduced-dose glucocorticoid plus rituximab regimen noninferior to the conventional high-dose glucocorticoid plus rituximab regimen in remission induction of antineutrophil cytoplasm antibody (ANCA)–associated vasculitis?

Findings  In this randomized clinical trial that included 140 patients with newly diagnosed ANCA-associated vasculitis, the proportion of patients with disease remission at 6 months was 71.0% in the reduced-dose glucocorticoid plus rituximab group and 69.2% in the high-dose glucocorticoid plus rituximab group, a difference that met the prespecified noninferiority margin of −20 percentage points.

Meaning  Among patients with newly diagnosed ANCA-associated vasculitis, a reduced-dose glucocorticoid plus rituximab regimen was noninferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission.

Abstract

Importance  The current standard induction therapy for antineutrophil cytoplasm antibody (ANCA)–associated vasculitis is the combination of high-dose glucocorticoids and cyclophosphamide or rituximab. Although these regimens have high remission rates, they are associated with considerable adverse events presumably due to high-dose glucocorticoids.

Objective  To compare efficacy and adverse events between a reduced-dose glucocorticoid plus rituximab regimen and the standard high-dose glucocorticoid plus rituximab regimen in remission induction of ANCA-associated vasculitis.

Design, Setting, and Participants  This was a phase 4, multicenter, open-label, randomized, noninferiority trial. A total of 140 patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage were enrolled between November 2014 and June 2019 at 21 hospitals in Japan. Follow-up ended in December 2019.

Interventions  Patients were randomized to receive reduced-dose prednisolone (0.5 mg/kg/d) plus rituximab (375 mg/m2/wk, 4 doses) (n = 70) or high-dose prednisolone (1 mg/kg/d) plus rituximab (n = 70).

Main Outcomes and Measures  The primary end point was the remission rate at 6 months, and the prespecified noninferiority margin was −20 percentage points. There were 8 secondary efficacy outcomes and 6 secondary safety outcomes, including serious adverse events and infections.

Results  Among 140 patients who were randomized (median age, 73 years; 81 women [57.8%]), 134 (95.7%) completed the trial. At 6 months, 49 of 69 patients (71.0%) in the reduced-dose group and 45 of 65 patients (69.2%) in the high-dose group achieved remission with the protocolized treatments. The treatment difference of 1.8 percentage points (1-sided 97.5% CI, −13.7 to ∞) between the groups met the noninferiority criterion (P = .003 for noninferiority). Twenty-one serious adverse events occurred in 13 patients in the reduced-dose group (18.8%), while 41 occurred in 24 patients in the high-dose group (36.9%) (difference, −18.1% [95% CI, −33.0% to −3.2%]; P = .02). Seven serious infections occurred in 5 patients in the reduced-dose group (7.2%), while 20 occurred in 13 patients in the high-dose group (20.0%) (difference, −12.8% [95% CI, −24.2% to −1.3%]; P = .04).

Conclusions and Relevance  Among patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, a reduced-dose glucocorticoid plus rituximab regimen was noninferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission at 6 months.

Trial Registration  ClinicalTrials.gov Identifier: NCT02198248

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